METHODS FOR TREATING OR PREVENTING TTR-ASSOCIATED DISEASES USING TRANSTHYRETIN (TTR) iRNA COMPOSITIONS

1 . (canceled)

2 . A method of improving at least one indicia of quality of life in a human subject suffering from a TTR-associated disease or at risk for developing a TTR-associated disease, the method comprising administering to the human subject a fixed dose of about 25 mg to about 50 mg of a double stranded RNAi agent, or salt thereof,

wherein the double stranded RNAi agent comprises a sense strand complementary to an antisense strand,

wherein the sense strand comprises the nucleotide sequence 5′-usgsggautiuCfAfUfguaaccaaga-3′ (SEQ ID NO: 10) and the antisense strand comprises the nucleotide sequence 5′-usCfsuugGfuuAfcaugAfaAfucccasusc-3′ (SEQ ID NO: 7),

wherein a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, or U, respectively; Af, Cf, Gf, and Uf are 2′-fluoro A, C, G, or U, respectively; and s is a phosphorothioate linkage, and

wherein the quality of life indicia is a Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) score, thereby improving the at least one indicia of quality of life in the human subject.

3 - 6 . (canceled)

7 . The method of claim 2 , wherein the human subject is a human subject suffering from a TTR-associated disease.

8 . The method of claim 2 , wherein the human subject is a human subject at risk for developing a TTR-associated disease.

9 . The method of claim 2 , wherein the human subject carries a TTR gene mutation that is associated with the development of a TTR-associated disease.

10 . The method of claim 2 , wherein the TTR-associated disease is selected from the group consisting of senile systemic amyloidosis (SSA), systemic familial amyloidosis, familial amyloidotic polyneuropathy (FAP), familial amyloidotic cardiomyopathy (FAC), leptomeningeal/Central Nervous System (CNS) amyloidosis, and hyperthyroxinemia.

11 . The method of claim 2 , wherein the human subject has a transthyretin-mediated amyloidosis (ATTR amyloidosis) and the method reduces an amyloid TTR deposit in the human subject.

12 . The method of claim 11 , wherein the ATTR amyloidosis is hereditary ATTR amyloidosis (h-ATTR amyloidosis).

13 . The method of claim 11 , wherein the ATTR amyloidosis is non-hereditary ATTR amyloidosis (wt ATTR amyloidosis).

14 . (canceled)

15 . (canceled)

16 . The method of claim 2 , wherein the double stranded RNAi agent, or salt thereof, is administered to the human subject via subcutaneous administration.

17 . The method of claim 16 , wherein the subcutaneous administration is self administration.

18 . The method of claim 17 , wherein the self-administration is via a pre-filled syringe or auto-injector syringe.

19 . (canceled)

20 . (canceled)

21 . The method of claim 2 , wherein the fixed dose of the double stranded RNAi agent, or salt thereof, is administered to the human subject once about every three months.

22 . The method of claim 2 , wherein the fixed dose of the double stranded RNAi agent, or salt thereof, is administered to the human subject once about every six months.

23 . (canceled)

24 . The method of claim 2 , wherein the double stranded RNAi agent, or salt thereof, is administered to the human subject at a fixed dose of about 25 mg.

25 . The method of claim 2 , wherein the double stranded RNAi agent, or salt thereof, is administered to the human subject at a fixed dose of about 50 mg.

26 . The method of claim 2 , further comprising administering to the human subject an additional therapeutic agent.

27 . (canceled)

28 . The method of claim 2 , wherein the 3′ end of the sense strand of the double stranded RNAi agent is conjugated to at least one ligand, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker.

29 . (canceled)

30 . The method of claim 28 , wherein the ligand is

31 . (canceled)

32 . The method of claim 30 , wherein the double stranded RNAi agent is conjugated to the ligand as shown in the following schematic

wherein X is O or S.

33 . The method of claim 2 , wherein the sense strand of the double stranded RNAi agent comprises the nucleotide sequence 5′-usgsggauUfuCfAfUfguaaccaaga-3′ (SEQ ID NO: 15) and the antisense strand of the RNAi agent comprises the nucleotide sequence 5′-usCfsuugGfuuAfcaugAfaAfucccasusc-3′ (SEQ ID NO: 7),

wherein a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, or U, respectively; Af, Cf, Gf, and Uf are 2′-fluoro A, C, G, or U, respectively; s is a phosphorothioate linkage; and

wherein the 3′ end of the sense strand of the double stranded RNAi agent is conjugated to a ligand as shown in the following schematic

wherein X is O.

34 . (canceled)

35 . The method of claim 2 , wherein the method results in a reduction of the Norfolk QoL-DN score by at least about 2.5.

36 . The method of claim 2 , wherein the method results in a reduction of the Norfolk QoL-DN score by at least about 3.0.

37 . The method of claim 2 , wherein the method results in a 0% increase of the Norfolk QoL-DN score.